Elucidation of signaling pathways involving magnetic field-driven remote cellular control

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Mundell, Jordan
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Electronic thesis
Chemical engineering
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External and remote control of signal transduction pathways can provide both on-demand and spatial control over cell function. This control can be used to address diseases where aberrant signaling occurs, including cancer, cardiovascular disorders, and neurodegeneration. Several methods to control signaling pathways have been developed, including chemogenetics, optogenetics, and more recently, magnetogenetics, that when coupled with recent advances in gene delivery offer potentially new therapeutic routes to address these diseases. Each of which aims to control cellular function by applying a different external stimuli, drugs, light, and magnetic fields, respectively. Chemogenetics uses designer small molecule drugs specifically to target genetically engineered cell receptors that regulate cellular pathways when activated, such as neuronal firing and inhibition. However, because chemogenetics requires a pharmacologic intervention, it is strongly dependent on drug pharmacokinetics and pharmacodynamics in vivo. Optogenetics uses specific wavelengths of light to activate light-sensitive ion channels. Unfortunately, invasive probes are required in vivo due to the poor penetration depth of light. Magnetogenetics was developed to circumvent these issues, providing spatial and temporal control over cell function while being truly remote due to the ability of magnetic fields to freely permeate through tissue. This was accomplished by tethering iron nanoparticles from endogenous ferritin to cation transmembrane channels (TRPV1 in particular). The ferritin acts as the target for the magnetic fields, resulting in channel gating, ion flux, and downstream effects. The work presented here aims to expand upon the magnetogenetics field by offering insights into the mechanism governing magnetogenetics. Initial hypotheses on how ferritin transduces magnetic fields into channel gating included thermal and mechanical effects, however, these theories have largely been disproven. Recent results have hypothesized a chemical mechanism involving production of reactive oxygen species (ROS) around ferritin. Here, the mechanism is further explored and elucidated. Magnetogenetic response was found to be highly dependent on field properties such as field strength and frequency. Use of several inhibitors explored the complex network of cellular pathways involved in magnetogenetics activation. Furthermore, a bioengineering approach was used to confirm the crucial role of ROS in platform stimulation and the necessity for TRPV1-ferritin tethering. Together, these results provide an important step in evolving the field of magnetogenetics to a level on par with predecessor field.
School of Engineering
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Rensselaer Polytechnic Institute, Troy, NY
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